Malaria remains a major cause of illness and death worldwide. Plasmodium vivax malaria is an especially important cause of morbidity in South America. Two major unresolved issues concerning the pathogenesis of P. vivax malaria are: 1) what molecules from the parasite activate the innate immune system and cause inflammation and, 2) what are the receptors that are ligated by these microbial products. Our studies suggest that Toll-like receptors (TLRs), acting primarily through the Myeloid Differentiation Factor 88 (MyD88) adaptor molecule, are critical for initiation of this early inflammatory response and pathogenesis of malaria. In addition, we have evidence of Nod-Like receptor (NLR) activation, inflammasome formation and processing of caspase- 1 in human patients during malaria. We hypothesize that upon P. vivax infection, innate immune receptors in phagocytes are responsible for the intense cytokinemia as a consequence of hyper-responsiveness of Toll-like receptors (TLRs), and the assembly of inflammasomes. However, the most basic details of malaria-related cytokinemia are not well understood, although our studies in P. falciparum allow us to construct a hypothetical model of disease surrounding the delivery of parasite DNA to innate immune sensors. We further hypothesize that the innate immune response results in priming of the innate immune system which triggers the production of cytokines via phagocytosis of nucleic acids of via formation of immune complexes. We will evaluate (i) the levels of circulating parasite DNA, anti-nucleic acid antibodies, as well as immunocomplexes (ICs); (ii) the immunostimulatory activity of DNA-containing ICs on triggering cytokine production and caspase-1 activation via nucleic acid sensing innate immune receptors expressed by phagocytes; and (iii) as indicative of malaria priming, we will look for the expression of genes related to the TLRs, NLRs and IFN signaling pathway as well as the responsiveness of peripheral blood mononuclear cells (PBMCs) from patients infected with P. vivax. Hence, we hope to define the contribution of ICs, pro-inflammatory priming, and inflammasomes on systemic inflammation observed during acute P. falciparum malaria. We hope to identify immunomarkers of disease, whose expression indicates checkpoints that are critical for the pathogenesis of P. vivax infection. Such knowledge should contribute to new insights on the molecular basis of inflammation during malaria and help to improve clinical management of malaria patients. Finally, this project will be done in collaboration with Dr. Carolina Gallego-Marin from CIDEIM (International Centre of Medical Research and Training) in Cali, Colombia, with the purpose of developing her career as an independent investigator in Colombia. The research will be performed primarily by the LMIC collaborator; initially 50% of the work will be done at CIDEIM and 50% in Massachusetts, and gradually the amount of time Dr. Gallego spends in South America will increase, with the ultimate goal of exporting cutting edge technology and expertise to the scientific community in Colombia.